The effects of parathyroid hormone (PTH) on the skeleton are complex and poorly understood. PTH can have both catabolic and anabolic effects on bone. On the 1 hand, chronic elevated PTH levels, as in patients with moderate to severe hyperparathyroidism, or with continuous infusion, has catabolic effects, particularly evident in the cortical bones. In contrast, in patients with mild hyperparathyroidism, or intermittent administration of PTH, has an anabolic effect, predominantly evident in the cancellous bone. However, the mechanisms that underlie the differential effects of PTH--on the cortical versus cancellous skeleton, in states of mild versus severe hyperparathyroidism, or with continuous versus intermittent administration--are yet unclear. A major hurdle in studying the mechanisms for PTH's dual actions has been the lack of an effective model system. Much of our current understanding has been based on in vitro systems. However, such systems lack in their ability to fully evaluate the influence of PTH-induced molecular and cellular changes on physiological regulation of bone formation and resorption and on architectural and biomechanical alterations in bone. The proposed studies will exploit a recently developed transgenic mouse model of hyperparathyroidism to overcome these limitations. By the age of 10 months, these mice develop mild hyperparathyroidism, which eventually progresses to chronic moderate to severe hyperparathyroidism. The first Specific Aim will characterize quantitative and qualitative effects of PTH excess on the cancellous and cortical bones in states of mild and moderate/severe hyperparathyroidism. The second Specific Aim will examine the effects of mild and severe HPT on trabecular osteoblast proliferation, osteoblast apoptosis and osteoclast formation. The outcome of these studies will be the characterization of an in vivo model system that can be effectively used in future studies to investigate the mechanisms of both, the anabolic and catabolic effects of PTH on bone. Given the recent use of PTH to treat osteoporosis, there is a critical need to better understand the mechanisms of its actions. [unreadable] [unreadable]